Genetic influences on vitamin D status and forearm fracture risk in African American children.

We sought to investigate the relationship between newly identified genetic variants and vitamin D levels and fracture risk in healthy African American (black) children. This case-control study included children of both sexes, ages 5 to 9 years, with and without forearm fractures. Serum 25-hydroxy vitamin D levels, bone mineral density, body mass index, and calcium/vitamin D intake were measured in 130 individuals (n = 60 cases and n = 70 controls). The 5 variants tested were located in the GC gene (rs2282679), in the NADSYN1 gene (rs12785878 and rs3829251), and in the promoter region of the CYP2R1 gene (rs2060793 and rs104741657). Associations between single nucleotide polymorphisms (SNPs) and vitamin D levels were tested using an analysis of covariance. Associations between SNPs and fracture status were tested using logistic regression. The GC gene variant was associated with vitamin D levels (P = 0.038). None of the SNPs were associated with fracture status in young blacks. These results suggest that the variants tested, which are associated with circulating vitamin D levels in whites, are not associated with fracture status in healthy black children. Additional research is required to discover the genetics of fracture risk in blacks.

Temporal pattern of gene expression and histology of stress fracture healing.

Loading of the rat ulna is an ideal model to examine stress fracture healing. The aim of this study was to undertake a detailed examination of the histology, histomorphometry and gene expression of the healing and remodelling process initiated by fatigue loading of the rat ulna. Ulnae were harvested 1, 2, 4, 6, 8, and 10 weeks following creation of a stress fracture. Stress fracture healing involved direct remodelling that progressed along the fracture line as well as woven bone proliferation at the site of the fracture. Histomorphometry demonstrated rapid progression of basic multicellular units from 1 to 4 weeks with significant slowing down of healing by 10 weeks after loading. Quantitative PCR was performed at 4 hours, 24 hours, 4 days, 7 days, and 14 days after loading. Gene expression was compared to an unloaded control group. At 4 hours after fracture, there was a marked 220-fold increase (P<0.0001) in expression of IL-6. There were also prominent peak increases in mRNA expression for OPG, COX-2, and VEGF (all P<0.0001). At 24 hours, there was a peak increase in mRNA expression for IL-11 (73-fold increase, P<0.0001). At 4 days, there was a significant increase in mRNA expression for Bcl-2, COX-1, IGF-1, OPN, and SDF-1. At 7 days, there was significantly increased mRNA expression of RANKL and OPN. Prominent, upregulation of COX-2, VEGF, OPG, SDF-1, BMP-2, and SOST prior to peak expression of RANKL indicates the importance of these factors in mediating directed remodelling of the fracture line. Dramatic, early upregulation of IL-6 and IL-11 demonstrate their central role in initiating signalling events for remodelling and stress fracture healing.

Congenital pseudarthrosis of the ulna and radius in two cases of neurofibromatosis type 1.

Two children with neurofibromatosis type 1 who presented at birth with congenital pseudarthrosis of the ulna and radius are described. The patients were treated with broad resections. As a consequence, the forearms were reduced in length. The osteotomies were stabilized in one patient first with endomedullary nailing and then with a free vascularized fibular graft. In the second patient the osteotomy was stabilized by external fixation. Using these techniques, rapid and excellent healing and normal function were achieved. In contrast to the lower extremity, reduction of the length of the forearm can be accepted to a certain extent. If necessary, an extension osteotomy can be performed at a later date.

Vitamin D receptor genotype and the risk of bone fractures in women.

Several studies have confirmed an initial report of a relation between bone density and polymorphic forms of the calcitriol (vitamin D) receptor gene, whereas others have failed to find an association. We examined whether variants of the vitamin D receptor gene are associated with the risk of bone fracture, using a nested case-control analysis within the Nurses' Health Study cohort. The study women all were Caucasian and were 43-69 years of age when they provided a blood sample. Cases included the 54 proximal femur (hip) fractures and 163 distal radius (forearm) fractures that occurred subsequent to the blood draw. Cases and controls were genotyped by polymerase chain reaction for the BsmI polymorphism. The BB genotype, previously associated with lower bone density, was associated with a more than twofold increased risk of hip fracture compared with the bb genotype. Risk was greater for women who were older, leaner, or less physically active or who had a lower calcium intake. The heterozygous genotype was not associated with any increased risk of hip fracture, and we observed little association between vitamin D receptor genotype and forearm fracture. This study supports an association between vitamin D receptor genotype and hip fracture. It also implies that modification by other risk factors may have contributed to the conflicting results from previous studies of vitamin D receptor genotype and femoral bone density.